The present invention relates to pharmaceutical compositions whose mechanisms of action include at least antagonism at the glycine site on the NMDA (N-methyl-D-aspartate) receptor complex, and to methods for prophylaxis, attenuation, or prevention of acute or chronic neuronal damage in various systemic or neurological diseases, conditions, or procedures.
The major excitatory neurotransmitters in the central nervous system are L-glutamine and L-aspartate. Classification of the excitatory receptors include the AMPA, kainate and NMDA receptors. The NMDA receptor is located on the neuronal cell surface and is composed of multiple binding sites which regulate Ca++ homeostasis. The glycine and glutamate binding sites are allosterically linked at the NMDA receptor complex. Glutamate is the principal excitatory neurotransmitter in the brain and has an integral role in neurologic function including cognition, memory, movement and sensation. Glutamate has also been implicated in the pathogenesis of multiple acute and chronic neurological diseases.
Felbamate (2-phenyl-1,3-propanediol dicarbamate) is a known pharmaceutical compound and is described in U.S. Pat. No. 2,884,444. Felbamate has multiple actions on the nerve cell of which one is a glycine site antagonist at the NMDA receptor. See U.S. Pat. Nos. 4,978,680; 5,082,861; 5,292,772; 4,868,327; and 5,256,690.
Felbamate is a modulator of NMDA function by a glycine site antagonist mechanism but has multiple mechanisms of action. These include interaction at the AMPA/kainate receptor, facilitating GABA function, modulation of the Na+ channel, interaction at both of the metabotropic and muscarinic receptors, as well as the L-type calcium channel.
Excessive stimulation of the NMDA receptor by excitatory amino acids or neurotoxic mediators of inflammation is believed to be the etiology of multiple acute and chronic neurological diseases. Sudden toxic elevations of glutamate in acute neurological disorders or increased nerve cell vulnerability by abnormal bioenergetic metabolism in chronic disorders are possible mechanisms. Thus, NMDA exictotoxicity may represent a final common pathway for neuronal death in both acute and chronic neurological disease.
Subsequent to the approval of Felbamate, in 1994 there were reports of a plastic anemia and hepatic failure. These adverse events may have been due to drug interaction.
One of the objects of the present invention is to provide compositions and methods for the treatment of acute and chronic disorders that involve excessive activation of the NMDA receptor.
Another object of the present invention is to provide a method for attenuation or prevention of neuronal cell death caused by excessive activation of the NMDA receptor by administering the drug prophylactically and chronically when the patient has asymptomatic or pre-clinical systemic or neurological disease.
Another object of the present invention is to provide compositions and methods effective to prevent, control, or attenuate acute and chronic neuronal injury and death from systemic or neurological disease.
A further objective of the present invention is to provide compositions and methods for the prevention and control of acute and chronic systemic or neurological disorders that involve excessive activation of the NMDA receptor, which compositions are relatively non-toxic, have a high degree of effectiveness and continue to produce a therapeutic response over a long duration of time.
An additional object of the present invention is the treatment of the chronic neulogical condition called spasticity by the administration of a compound that has at least the property of antagonizing the glycine-site at the NMDA receptor.
The subject invention relates to methods for creating acute and chronic neurological diseases and educing or preventing neuronal cell death in both systemic and neurological diseases, in mammals including humans, employing a drug whose mechanism of action is at least partially mediated through a strychnine-insensitive glycine receptor mechanism. The antagonists are administered intravenously or orally, acutely or chronically, to prevent or attenuate neuronal damage and death. Advantageously, the drug is administered prophylactically and chronically when the patient is at risk for asymptomatic or pre-clinical systemic or neurological disease, or when the patient undergoes a vascular procedure which have a high risk for neuronal cell injury or death.
This invention also relates to a method of reducing or preventing neuronal cell injury or death when the glycine-site antagonist, felbamate, is administered prophylatically and chronically in a mammal, or a human.
This invention also relates to a method of reducing or preventing neuronal cell injury or death when the glycine-site antagonist, felbamate, is used as monotherapy or polytherapy, in a human or mammal.